OTC analgesics and drug interactions: clinical implications

Inhibition of COX by aspirin and other NSAIDs interferes with the production of protective mucosal PGs [9]. This mechanism likely explains the increased incidence of gastric ulcers and upper GI bleeding with use of NSAIDs. Listed below are several risk factors that increase the likelihood of developing GI toxicity with NSAIDs use [11‐13]:

• Advanced age

• History of GI events

• Increased NSAID dose or multiple NSAID use

• Concomitant aspirin use.

Elderly patients are at greater risk of developing GI complications and often have comorbidities that require analgesic treatment [14]. Thus, careful monitoring of the amount of OTC and prescription NSAID consumption is imperative in the management of elderly patients. To minimize GI adverse events, proton-pump inhibitors (PPIs) or other gastroprotective agents may be useful for patients who require NSAIDs for anti-inflammatory therapy and are at risk for increased GI events [14, 15].

COX inhibition by aspirin results in a dramatic reduction of gastroprotective PGs in the GI tract, which explains the dose-dependent increase in GI adverse effects with higher doses of aspirin (odds ratio [OR] = 1.5 – 3.1) [16‐18]. Several studies have reported that the use of enteric-coated and buffered low-dose aspirin does not appear to decrease the risk of GI adverse events (relative risk [RR], range = 2.3–2.7 {1.6–3.2}) [18‐20]. Similarly, traditional NSAIDs are also associated with a 2- to 4-fold increased risk of GI side effects [11, 16]. A summary of the risks for upper GI bleeding from a case-control study that included aspirin, acetaminophen, and ibuprofen, is shown in Figure 1[16]. Increased risk of GI adverse effects was observed with use of aspirin and ibuprofen, but not with acetaminophen.

Adverse GI effects are further compounded by the use of more than one agent and with higher NSAID doses [11, 13, 16]. Concomitant use of aspirin and traditional NSAIDs can double the risk of GI toxicity, as reported in a study of low-dose aspirin used for CV prophylaxis [18]. The standardized incidence rate of upper GI bleeding was 2.6 (95% confidence interval [CI]: 1.8–3.5) for patients using low-dose aspirin alone and 5.6 (95% CI: 4.4–7.0) for those using low-dose aspirin in addition to traditional NSAIDs. Gutthann and colleagues [11] reported much higher incidence of upper GI bleeding or perforation in patients who used multiple NSAIDs (adjusted OR = 9.0 [95% CI: 5.9–13.6]).

Although there is little inherent risk of GI events with anticoagulant use, several studies have shown that concomitant treatment with aspirin and other NSAIDs can increase the risk of GI hemorrhage and perforation [12, 13]. This may be linked to the impairment of platelet aggregation induced by aspirin and nonselective NSAIDs [21]. A study by Shorr and colleagues [12] reported a nearly 13-fold increase (95% CI: 6.3–25.7) in risk of developing hemorrhagic peptic ulcer disease with concurrent use of NSAIDs and anticoagulants in patients aged 65 years and older. A similar study conducted in patients aged 25 to 80 years reported an adjusted relative risk (RR) of 6.4 (95% CI: 2.8–14.6) for developing upper GI bleeding and perforation in patients using an NSAID and an anticoagulant, compared with those who had not received either drug [13].

Corticosteroids may cause decreased gastric mucus production and delayed healing of NSAID-induced erosions [22]. The use of corticosteroids in patients not receiving NSAIDs is linked to a modest increase in GI events (OR range, 1.1 – 2.3) [11, 22]. Nevertheless, there is wide reporting in the literature of a dramatic increase in the risk of adverse GI effects, including ulceration and hemorrhage, with concomitant current use of corticosteroids and NSAIDs (OR range, 2.2 – 14.6, in various studies) [11, 13, 22]. Piper and colleagues (1991) demonstrated that patients receiving corticosteroids (eg, cortisone 25 mg, hydrocortisone 20 mg, prednisolone 5 mg, prednisone 5 mg) in combination with NSAIDs had a 15 times greater risk for peptic ulcer disease than that of nonusers of either drug. Thus, although corticosteroids may not inherently increase the risk of GI toxicity, they exacerbate the risk posed by NSAIDs by delaying the healing of NSAID-induced ulcers.

Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased risk of upper GI bleeding [23, 24]. Serotonin is essential in initiating the hemostatic response of platelets to vascular injury [25]. By blocking platelet uptake of serotonin, SSRIs may attenuate their function. Thus, SSRIs may impair hemostatic function and exacerbate underlying GI conditions when used concomitantly with drugs that cause GI ulceration and bleeding (eg, NSAIDs) [23]. A recent case-control study reported a low risk of GI adverse events with use of SSRIs (OR = 1.30 [95% CI: 1.13–1.50], compared with nonuse of SSRIs or NSAIDs), but confirmed an increased risk with concomitant use of NSAIDs (OR = 4.19 [95% CI: 3.30–5.31], compared with nonuse of either drug) [25].

Acetaminophen may be an effective alternative to NSAIDs for patients who require an analgesic and who are on concomitant aspirin, anticoagulant, corticosteroid, or SSRI therapy. Patients should be educated on the risk factors for developing adverse GI events with use of NSAIDs and on appropriate ways to minimize further risks.

Many patients use low-dose aspirin for primary or secondary prevention of myocardial infarction and stroke. Aspirin induces irreversible COX-1 inhibition in the platelet, a process that in turn inhibits the formation of thromboxane A₂ and prevents platelet aggregation (Figure 2) [2, 26]. Because aspirin completely inactivates platelet COX-1, antiplatelet benefits last for the lifetime of the platelet and are only attenuated by the regeneration of new platelets. As a result, even low doses of aspirin may provide beneficial CV effects. Nevertheless, recent studies have shown that traditional NSAIDs may interfere with the antiplatelet effects of aspirin by providing competition for the platelet COX-1 binding site [26‐28]. This may limit the utility of aspirin as a cardioprotective agent in patients who require certain NSAIDs to manage pain effectively.

Numerous studies have shown that ibuprofen interferes with the antiplatelet effects of aspirin [26, 28, 29]. Catella-Lawson and colleagues [26] evaluated whether the antiplatelet effects of aspirin were mitigated by the concurrent use of ibuprofen, diclofenac, rofecoxib, and acetaminophen. Ibuprofen, administered as a single 400 mg dose given before aspirin (81 mg) or as 3 400 mg doses after a single 81 mg dose of aspirin, blocked the irreversible inhibition of platelet aggregation by aspirin. In contrast, the concomitant administration of rofecoxib (25 mg once daily), diclofenac (75 mg twice daily), or acetaminophen (1000 mg once daily) – administered either before or after a dose of aspirin – did not affect the inhibition of platelet aggregation by aspirin. Another study reported an increased risk in recurrent acute myocardial infarction with prolonged use of ibuprofen and aspirin compared with use of aspirin alone (hazard ratio for duration of exposure for at least 60 days = 1.83 [0.76–4.42]) [28]. Patients who take ibuprofen in addition to low-dose aspirin for CV prophylaxis should be mindful of the potential for drug interactions that may undermine the cardioprotective benefits of aspirin.

Recent studies on the effect of naproxen on platelet and vascular prostanoid inhibition have yielded inconclusive results [27, 30]. Unlike aspirin, naproxen inhibits prostacyclin synthesis, the clinical implication of which is currently unknown. Nonetheless, naproxen is commonly suggested as an alternative to ibuprofen in patients with established CV risk who take daily low-dose aspirin for CV prophylaxis [15]. Other alternatives for analgesia for patients receiving long-term low-dose aspirin therapy include acetaminophen or other NSAIDs such as diclofenac, which do not preferentially inhibit COX-1. Because acetaminophen is a weak inhibitor of COX-1, it does not interfere with aspirin-mediated antiplatelet effects [7].

By inhibiting prostaglandin synthesis, NSAIDs can induce sodium retention and vasoconstriction [31]. Clinical studies have linked the use of NSAIDs to elevated blood pressure, particularly in patients with a history of hypertension who are already on antihypertensive medications [32‐35]. In a meta-analysis of randomized trials studying the effect of NSAIDs on blood pressure, NSAIDs raised mean blood pressure by 5.0 mm Hg [34]. Patients who were concomitantly using β-blockers experienced greater elevations in mean blood pressure (6.2 mm Hg) compared with those using either vasodilators or diuretics. Careful monitoring of blood pressure and cardiac function is therefore recommended for hypertensive patients when initiating NSAID therapy. The potential risk of CV events with use of NSAIDs has been studied extensively in recent years. In 2005, the US Food and Drug Administration issued a request that manufacturers of all nonaspirin NSAIDs, including COX-2 inhibitors, revise package inserts to include a black box warning highlighting the increased risk for CV events and GI bleeding with use of these drugs [36].

Other medications may have adverse interactions when taken in conjunction with OTC analgesics (Table 1). Aspirin, particularly in combination with anticoagulation therapy, has been shown to increase the risk of intracerebral hemorrhages (ICH) [37]. Although ICH is an uncommon adverse effect of aspirin, the morbidity associated with this condition makes it a clinically relevant issue. Concomitant use of NSAIDs and antidiabetic agents, particularly sulfonylureas, may increase the risk of transient hypoglycemia [38]. NSAIDs have also been shown to increase risk of lithium and methotrexate toxicity by increasing drug concentrations to unsafe levels [39‐41]. Monitoring drug concentrations and adjusting dosages when necessary may reduce the likelihood of adverse drug interactions with use of OTC analgesics.